Destructive periodontitis is associated with infections by A. actinomycetemcomitans and P. gingivalis. Their ability to invade epithelial cells makes them difficult to treat by mechanical debridement alone, but antimicrobial agents enhance their elimination. Fluoroquinolones and tetracyclines are very useful because they are cell-permeant and have favorable activity. Through mechanisms that remain unclear, both have an unusual ability to be taken up by cells and both attain higher levels in gingival fluid (GF) than in serum. Recent studies suggest that active transport plays important roles. Cultured epithelial cells take up both agents by active transport, and gingival connective tissue also accumulates fluoroquinolones (attaining levels that are higher than those in serum). We hypothesize that gingival fibroblasts possess active transporters that allow them to accumulate fluoroquinolones and tetracyclines in the gingival connective tissue. The resulting distribution of these agents is responsible for the high levels they attain in GF. Epithelial cells in the gingiva also take up these agents, providing access to intracellular pathogens. The objective of this proposal is to define the mechanisms by which fluoroquinolones and tetracyclines are transported and concentrated in the gingiva. Specific aim 1 is to characterize and identify the transport systems by which gingival fibroblasts and epithelial cells take up these agents. Specific aim 2 is to determine whether transport of these agents is modulated by growth factors or cytokines. Specific aim 3 is to compare the distribution of fluoroquinolones and tetracyclines in serum, gingival connective tissue, and gingival fluid. Insight gained from this work could facilitate the development of new therapeutic approaches that exploit these transport systems. Strategies that optimize the uptake and distribution of antimicrobial agents should enhance the elimination of invasive pathogens from the periodontium and other types of mucosa.